: Nonsyndromic orofacial clefts (OFCs) of the lip with or without cleft palate (CL/P) or of the palate only (CPO) comprise a significant proportion of human birth defects (about 1/700 live births worldwide) requiring surgical, nutritional, dental, speech, medical and behavioral interventions and thus impose substantial public health, economic, and personal burdens. During the previous funding periods of this project, we achieved all our delineated goals and unequivocally established a rich phenotyping paradigm that our research group has developed over the last decade. Our phenotyping protocol can help define mechanisms that lead to OFCs and more precisely predict individual risks for these defects. Subclinical expressions of OFC (e.g., subtle speech abnormalities) that are distributed within affected families can reveal clues about etiology. Numerous genes/loci have now been identified for overt OFC, based largely on genome-wide association studies resulting from the current funding period.